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Department of Physiology, University of Arizona, and The Benjamin W. Zweifach Microcirculation Laboratories, Department of Veterans Affairs Medical Center, Tucson, Arizona 85723
The modulation of endothelial barrier function is thought to be
a function of contractile tension mediated by the cell cytoskeleton, which consists of actomyosin stress fibers (SF) linked to focal adhesions (FA). We tested this hypothesis by dissociating SF/FA with
Clostridium botulinum exoenzyme C3
transferase (C3), an inhibitor of the small GTP-binding protein RhoA.
Bovine pulmonary artery endothelial cell (EC) monolayers given C3, C3 + thrombin, thrombin, or no treatment were examined using a
size-selective permeability assay and quantitative digital imaging
measurements of SF/FA. C3 treatment disassembled SF/FA, stimulated
diffuse myosin II immunostaining, and reduced the phosphotyrosine (PY)
content of paxillin and 130- to 140-kDa proteins that included
p125FAK. C3-treated monolayers
displayed a 60-85% decline in F-actin content and a
170-300% increase in EC surface area with enhanced endothelial
barrier function. This activity correlated with reorganization of
F-actin and PY protein(s) to 
-catenin-containing cell-cell junctions. Because C3 prevented the thrombin-induced formation of
myosin ribbons, SF/FA, and the increased PY content of proteins, these
characteristics were Rho dependent. Our data show that C3 inhibition of
Rho proteins leads to cAMP-like characteristics of reduced SF/FA and
enhanced endothelial barrier function.
Clostridium botulinum exoenzyme C3
transferase; immunofluorescent digital imaging; stress fibers; myosin; -catenin
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